Hudson Freeze

..By assessing the occurrence of a series of N-glycosylation-compromising alleles in multi-genic diseases, it may be possible to determine whether impaired glycosylation is a risk factor or a major determinant underlying their pathology...

..Although most of the deficiencies observed in CDG patients are only partial, the severity of the clinical manifestations signifies the relevance of protein N-glycosylation and shows the importance of defined glycan structures...

..This metabolic perspective may help explain some of these observations and guide the development of other vertebrate models of glycosylation disorders that can respond to dietary manipulation...

..This surprising finding makes identifying their defects more challenging, but the defects and associated clinical manifestations of these patients suggest that the N-glycosylation pathway has some secrets left to share...

..As more glycosylation disorders and patients with these disorders are identified, the functions of the glycome are starting to be revealed...

..Investigators designing model systems to study human glycosylation disorders may want to construct strains with several heterozygous hypomorphic alleles in rate-limiting steps in the glycosylation pathway...

..2002, this issue) use one to rescue designer mice unable to make GDP-Fucose. Dietary fucose enters a salvage pathway and spares the mice. Sound simple? Not so. Unknown genetic factors determine life or death...

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..These results indicate that carboxylated N -glycans on RAGE play an important functional role in amphoterin-RAGE-mediated signalling...

..Glycosylation-deficient cell and animal models are needed to determine which individual or combined approaches improve glycosylation and may be suitable for preclinical evaluation...

..Intracranial hemorrhage in a term neonate without a potential precipitating factor represents yet another clinical feature that should raise the suspicion for a congenital disorder of glycosylation...

..It specifically blocked activation of NF-kappaB p65 in lamina propria cells of colitic mice and in activated macrophages. These results indicate that carboxylate-glycan-dependent pathways contribute to the early onset of colitis...

..5 Mpi(-/-) embryos where Man-6-P increased more than 10 times, and ATP decreased by 50% compared with Mpi(+/+) littermates. Because Mpi ablation is embryonic lethal, a murine CDG-Ib model will require hypomorphic Mpi alleles...

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..These cases represent a new type of CDG in which the molecular defect lies in a protein that affects the trafficking and function of the glycosylation machinery...

..Clinicians are encouraged to test such patients for abnormal Tf glycosylation by ESI-MS...

..Lentiviral-mediated complementation with normal COG8 corrected mislocalization of other COG proteins, normalized sialylation and restored normal BFA-induced Golgi disruption. We propose to call this new disorder CDG-IIh or CDG-II/COG8...

..Thus, we conclude that the DPAGT1 gene defects are responsible for the CDG symptoms in this patient. Hum Mutat 22:144-150, 2003...

..These findings show that RAGE, carboxylated glycans and S100A8/A9 play essential roles in tumor-stromal interactions, leading to inflammation-associated colon carcinogenesis...

..The mutation disrupted the hetero-octomeric COG complex and altered both N- and O-linked glycosylation. Here we present clinical and biochemical data from a second family with the same mutation...

..Congenital disorders of glycosylation should be considered for children with undiagnosed multi-system disease including neurodevelopmental delay, skeletal dysplasia, immune deficiency, male genital hypoplasia, and cardiomyopathy...

..From these data, we conclude that PMI-null cells can salvage mannose from both endogenous and external glycoconjugates via lysosomal and nonlysosomal degradation pathways...

..The defect is corrected by introduction of a normal ALG3 cDNA. CDG should be ruled out in all patients with severe seizures and failure to thrive. (c) 2007 Wiley-Liss, Inc...

..Furthermore, a liposome reconstitution functional assay showed that GLUT11-L has glucose transport activity...

..These changes can be used to indicate when a protein has passed a particular subcellular location. This unit details some of the methods used to track a protein as it traffics from the ER to the Golgi toward its final location...

..This study provides evidence that enzymatic steps regulating N-linked glycosylation are novel targets for developing approaches to sensitize tumor cells to cytotoxic therapies...

..We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients...

..In this review we will discuss the individual syndromes, with focus on their neuronal involvement, available and possible treatments, and future directions...

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..Screening for CDG should be considered in children with relatively mild neurologic impairment, especially if they have suggestive findings such as cerebellar hypoplasia and abnormal fat distribution...

..Interestingly, the ortholog of GLUT14 is not found in mice. The multiple duplications of GLUT genes suggest that the GLUT family probably emerged by gene duplications and mutations during evolution in different lineages...

..The affinity purification procedure is fully automated, and the mass spectrometric analysis is multiplexed in a fashion that is suitable for high-throughput applications...

..Thus, it is unclear whether c.391T>C causes CDG-Ic or contributes to the symptoms. Genotyping additional patients with CDG-like symptoms will be required to resolve this issue...

..We therefore conclude that a combination of developmental delay, low IgG, and genital hypoplasia should prompt CDG testing...

..CONCLUSIONS: Our findings underscore the importance of proper glycosylation in several major organ systems and emphasize that CDG should be ruled out in patients with persistent hyperinsulinemic hypoglycemia of unknown etiology...

..These results demonstrate that mammalian cells synthesize complex-type N-glycans with glutamate linked to their antennae, further expanding their potential for covalent or ionic interactions...

..However, even in adulthood, this patient shows normal magnetic resonance imaging of the brain...

..These results validate the general concept of using pro-Man-1-P substrates as potential therapeutics for CDG-I patients...

..2p32.3)] and found no structural abnormalities in the father, suggesting a de novo event. Our findings extend the causes of CDG to larger DNA deletions and identify the first Japanese CDG-Ic mutation...

..Transferrin analysis showed only hyposialylation, but analysis of total serum N-glycans indicated loss of additional sugars, arguing that the latter generates a more informative picture to search for the primary defect...

..Soluble heparin fully compensated for HS loss, providing a reasonable explanation for patient favorable response to heparin therapy...

..We speculate that this type of variant may be implicated in other multi-factorial disorders that involve N-glycosylation...

..PUBLIC HEALTH RELEVANCE: We will study the first mouse model of a rare human genetic disorder in protein glycosylation, offer a likely therapy, and apply the model/therapy to treat other human glycosylation disorders. ..

..Analysis of glycosylation-deficient patients will broaden our understanding ob both glycobiology and its immediate application to human glycosylation diseases. ..

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..The results could provide a fundamental understanding of how PLE develops, identify Fontan patients genetically at risk for developing PLE, and provide insights to new therapeutics for this enigmatic rare disease. ..

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..In the long run, we want to understand their physiological and molecular basis of new disorders and provide underpinnings for patient therapy. ..

..We propose to make a mouse model of PLE and test a novel therapy developed in our laboratory. Our long-range goal is to identify at-risk patients and provide a therapy for them. ..

..Since this meeting immediately precedes the annual meeting of the Society for Glycobiology, it will increase the chances of recruiting glycobiologists to explore the various types of human glycosylation disorders. ..

..In some cases, mannose may be a therapeutic dietary supplement. A mannose supplementation trial for CDGS patients is now underway. ..

..The impact of solving these structures could be quite substantial. However, in the past, we have had difficulty establishing this structure, and therein lies the risk in this project and why it responds to PA-97-049. ..